During our initial funding period, we examined the mechanisms by which volume overload versus pressure overload caused hypertrophy. We found that despite severe volume overload, there was no increase in protein synthesis rate and that hypertrophy occurred by accumulation due to a decrease in degradation rate. This mechanism produced substantially less hypertrophy than in pressure overload where an increase in protein synthesis rate causes robust cardiac growth. The inadequate hypertrophy in mitral regurgitation, in myocardial infraction and in even some subjects with aortic stenosis, leads to increased wall stress and cardiac dilatation. Although cardiac dilatation initially permits the left ventricle to eject an increased stroke volume, dilatation eventually leads to increasing wall stress, and left ventricular dysfunction. Building on our observations during the first funding period we will now explore a key mechanism leading to the maladaptive situation of cardiac dilatation with increased wall stress. We will test the hypothesis that when there is inadequate hypertrophy to normalize diastolic wall stress, dilatation occurs and this dilation is in large part due to activation of matrix metalloproteases (MMP's). Specific aims of the current funding period are to 1). to examine matrix metalloprotease activity in five situations: a) normal dogs, b) dogs with aortic stenosis manifesting adequate hypertrophy, and no dilatation, c) dogs with aortic stenosis, inadequate hypertrophy, and cardiac dilatation, d) dogs with myocardial infarctions and dogs with mitral regurgitation, 2) to examine extracellular matrix and collagen architecture in connection with MMP activation, 3) to use MMP inhibitors to prevent activation and remodeling, and 4) to identify mechanisms controlling MMP activity. Using our models of human diseases we will define one of the major mechanisms of cardiac dilatation, will establish the regulation of MMP's and will further test our hypothesis by inhibiting dilatation with an MMP inhibitor. These studies will enhance both the scientific understanding of cardiac remodeling and also will address a major clinical problem causing significant cardiac mortality and morbidity.